The present invention relates to the use of calcium modulators in the treatment of cardiovascular and cerebral toxicity in mammals including man.
Calcium modulators are compounds that effect the transport of calcium through cellular membranes. Because of the several mechanisms for calcium transport, and the potential for multiple regulatory sites associated with some of these mechanisms, compounds of diverse structure have been found to be effective as calcium modulators. For example, reported calcium modulators include diphenylpiperazines such as verapamil and its derivatives, lidoflazine, cinnarizine and flunarizine; benzothiazepines such as diltiazem; dihydropyridines such as nifedipine, nitrendipine, nimodipine, nicardipine and BaK8644; and other structures such as bepridil, prenylamine and perhexiline. D. Wellans, "Twenty-Seven Calcium Entry Blockers in Cardiovascular and Cerebral Dysfunction" in Calcium Entry Blockers in Cardio Vascular and Cerebral Dysfunction, T. Godfraind et al. editors pp. 25-42 (1984).
As can be seen from the structures of the known calcium modulators shown in FIG. 1, the activity of a compound as a calcium modulator is not clearly associated with a particular type of structure. It has been established, however, that compounds that inhibit in vitro constriction of arteries induced by neurotransmitters such as norepinephrine, noradrenaline, and acetylcholine will generally act as calcium modulators in vivo. Fleckenstein, A. Calcium Antagonism in the Heart and Smooth Muscle, John Wiley and Sons, N.Y., (1983).